JP2000309545A - Treatment for age-related behavior disorder of companion animal and composition for the treatment - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for treating age-related behavior disorders, such as cognitive dysfunction syndrome and involutional melancholia, of a companion animal, by administering an effective dose of an acetylcholinesterase inhibitor. SOLUTION: This method for treating age-related behavior disorders comprises administering an acetylcholinesterase inhibitor, preferably, a compound of formula I R1 and R2 are each H, a 1-6C alkoxyl, benzyloxy, phenoxy or the like, or R1 and R2 each bond to the adjacent carbon atom to form a group of formula II (R3 is H or a 1-6C alkyl; J is O or the like; Q is O, S or the like) together with the carbon atom bonded with R1 and R2; X is O or S; Y is (CH2)m [(m) is 1-3]; L is phenyl or the like; R7 and R8 are each H, a 1-6C alkyl or the like), for example, 5,7-dihydro-7-methyl-3-[2-[1-(phenylmethyl)-4- piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one. The compound is preferably administered at a dose of about 0.001-5 mg/kg/day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to methods and compositions useful for treating cat and dog age-related behavioral disorders.

[0002]

TECHNICAL FIELD The cognitive dysfunction syndrome (CD)
S) is an age-related behavioral disorder observed in cats and dogs due to cognitive decline that cannot be attributed to non-cognate common medical conditions, such as tissue overgrowth, infection, or organ failure. Characterized. Symptoms of age-related behavioral disorders, such as CDS, in dogs include memory loss, which may be disorientation and / or confusion, altered interactions with family members, altered sleep-wake cycles, decreased activity levels, And the onset of frequent inappropriate excretion.
Similar symptoms are observed in cats with CDS.

[0003] The cause of CDS is unknown. Studies show that the symptoms increase with age, and that many pathological changes occur in aging dogs and cats and can theoretically be induced in CDS. One such change that has been linked to canine CDS is the formation of β-amyloid plaque. See also: Cummings, BJ et al., Neurobio.
l. Learning & Memory 66: 11-23 (199
6). Another change is the diminished activity of several neurotransmitters, such as acetylcholine, serotonin, norepinephrine, and dopamine. See, for example, Ruehl, WW, et al., Psychopharmacology of Animal.
Behavior Disorders, Dodman, NH and Shuste
r, L.) (Boston, 1998) 283-304.
Yet other potential causes of CDS include, but are not limited to, increased monoamine oxidase B activity and oxidation of central nervous system lipid membranes. See, for example, Corey-Bloom, J. et al., Monoamine Ox.
Lidaseman Inhibitors in Neurological Diseases (Lieberman, A.)
1994) 279-294; and Finnegan
ann, KT) Monoamine Oxidase Inhibitors in Neurol
ogical Diseases (monoamine oxidase inhibitors in neurological diseases) Lieberman, A.
(New York, 1994) 210-216.

Whatever the cause of the CDS, it has a dramatic effect on the health and well-being of the animals affected. In addition, the enjoyment of cats or dogs suffering from CDS has been increasing as the disease has become more severe and its symptoms,
For example, it may decrease as depression symptoms, anxiety, and / or poor general health are more severe. Thus, methods of treating, controlling, and / or preventing age-related behavioral disorders, such as CDS, are desired.

[0005]

SUMMARY OF THE INVENTION The present invention is directed to a method for treating age-related behavioral disorders in pet animals. The present invention is further directed to a method of treating a condition associated with an age-related behavioral disorder in a companion animal.

[0006]

SUMMARY OF THE INVENTION A first aspect of the present invention is a method of treating an age-related behavioral disorder in a companion animal, wherein the companion animal in need of such treatment is provided with a therapeutically effective amount of an acetylcholinesterase inhibitor. Administration. This embodiment is useful for certain age-related behavioral disorders, for example,
Methods of treatment include, but are not limited to, cognitive dysfunction syndrome and degenerative depressive symptoms.

A second aspect of the present invention is a method for improving the recognition process of a pet animal, which comprises administering to a pet animal in need of such improvement an acetylcholinesterase inhibitor in an amount sufficient to improve the recognition process. It is characterized by doing.

[0008] A third aspect of the present invention is a method of treating amnesia in a companion animal, comprising administering to the companion animal in need of such treatment an effective amount of an acetylcholinesterase inhibitor.

A fourth aspect of the present invention is a method of treating disorientation or confusion in a companion animal, comprising administering to the companion animal in need of such treatment a therapeutically effective amount of an acetylcholinesterase inhibitor. Features.

[0010] A fifth aspect of the present invention is a method of improving the social character of a companion animal, comprising administering to the companion animal in need of such improvement a therapeutically effective amount of an acetylcholinesterase inhibitor. .

[0011] A sixth aspect of the present invention is a method of adjusting the sleep-wake cycle of a pet animal, comprising administering to the pet animal in need of such adjustment a therapeutically effective amount of an acetylcholinesterase inhibitor. I do.

A seventh aspect of the present invention is a method for treating inappropriate excretion of a pet, comprising administering to the pet in need of such treatment a therapeutically effective amount of an acetylcholinesterase inhibitor. And

In a preferred embodiment of the present invention, the companion animal is a cat or a dog. In a preferred embodiment of the present invention, the acetylcholinesterase inhibitor is a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof:

[0014]

Embedded image

[Wherein R¹And R²Are each
Independently, hydrogen, (C₁-C₆) Alkoxy, benzylo
Xy, phenoxy, hydroxy, phenyl, benzyl,
Halo, nitro, cyano, -COR⁵, -COOR⁵, −
CONHR⁵, -NR⁵R⁶, -NR⁵COR⁶, -O
CONR⁵R⁶, -NHCOOR⁵, (C₁-C₆A)
Alkyl (the alkyl is one to three fluorine atoms
Optionally substituted), SO_pCH ₂-Phenyl or
Is SO_p(C₁-C₆) Alkyl wherein p is 0, 1 or
Is 2), pyridylmethyloxy or thienylmethylo
Xy, 2-oxazolyl, 2-thiazolyl, and ben
Selected from the group consisting of zensulfonamides;
The phenoxy, benzyloxy, phenyl, ben
The phenyl moiety of the jyl and benzenesulfonamide groups,
The pyridylmethyloxy or thienylmethyloxy
Pyridyl and thienyl moieties of the group
Oxazolyl of the sazolyl and 2-thiazolyl groups and
The thiazolyl moiety is a halo, (C₁-C₄) Alkyl,
Trifluoromethyl, (C₁-C₄) Alkoxy, shea
Independently selected from the group consisting of nitro, nitro and hydroxy
May be substituted by one or two substituents
Or R¹And R²Is attached to the adjacent carbon atom,
Together with the carbon atoms to which they are attached, formula (2):

[0016]

Embedded image

(Wherein, R³Is hydrogen or (C₁
-C₆) Alkyl; J is oxygen, sulfur or NR⁴R
⁴Is hydrogen or (C₁-C₄) Alkyl; and Q is an acid
Element, sulfur, NH, CHCH₃, C (CH₃)₂, -C
H = CH- or (CH₂) ₁Where l is 1
Which is an integer of 3) to form a group represented by the formula:

X is oxygen or sulfur; Y is-(C
_{H 2) m -, - CH} = CH (CH 2) n -, - NR
⁴ _{(CH 2) m} -, or -O _{(CH 2) m} - and is,
Wherein n is an integer from 0 to 3 and m is an integer from 1 to 3;

R ⁵ and R ⁶ are each independently hydrogen,
(C ₁ -C ₆ ) alkyl, phenyl, and benzyl; wherein the phenyl and the phenyl portion of the benzyl group are fluoro, chloro, bromo, iodo,
(C ₁ -C ₄ ) alkyl, trifluoromethyl, (C ₁
-C ₄₎ alkoxy, cyano, one or the two substituents may be substituted independently selected from the group consisting of nitro and hydroxy; or, NR ⁵ R ⁶ is 4-membered ring together or 5-membered ring is formed, in which case, one atom of the ring is nitrogen and the others are carbon, are oxygen or nitrogen; or -NR ⁵ COR ⁶ is 4 to 5-membered ring together Form a lactone ring;

L is phenyl, phenyl- (C₁-C₆)
Alkyl, cinnamyl or pyridylmethyl;
However, the phenyl and phenyl- (C₁-C₆A)
The phenyl moiety of alkyl is (C₁-C₆) Alkyl, (C
₁-C₆) Alkoxy, (C ₁-C₄) Alkoxycar
Bonil, (C₁-C₆) Alkylcarbonyl, —OCO
NR⁵R⁶, -NHCOOR⁵, And the group consisting of halo
With one to three more independently selected substituents
Or L is of the formula (3):

[0021]

Embedded image

(Wherein, b is an integer of 1 to 4;
R ⁹ and R ¹⁰ are each independently hydrogen, (C ₁ -C
₄ ) selected from alkyl, halo, and phenyl;
E and F are independently -CH- or nitrogen; and G is oxygen, it is a sulfur or NR ^4; provided that when E and F are both nitrogen, it is assumed that one of ^{R 9} and ^{R 10} is absent ); And

R ⁷ and R ⁸ are independently hydrogen, (C _1-
C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkylcarbonyl, and (C ₁₎
-C ₆ ) alkoxy; provided that the (C ₁ -C ₆ ) alkoxy is not bonded to the carbon adjacent to the nitrogen].

In a more preferred embodiment of the present invention, the compound of formula (1) is selected from the group consisting of: 5,7-dihydro-7-methyl-3- [2
-[1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,2-benzisoxazol-6-one; 5,7-dihydro-7-ethyl- 3- [2- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,
2-benzisoxazol-6-one; 5,7-dihydro-3- [2- [1- (2-chloro-5-thiophenmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5 -F] -1,2-benzisoxazole-6
ON; 5,7-dihydro-3- [2- [1- (2-methyl-4-thiazolemethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,2-benz Isoxazol-6-one; 3- [2- [1- (3-bromophenylmethyl) -4-piperidinyl] ethyl]-
5,7-dihydro-6H-pyrrolo [4,5-f] -1,
2-benzisoxazol-6-one; 3- [2- [1
-(4-bromophenylmethyl) -4-piperidinyl]
Ethyl] -5,7-dihydro-6H-pyrrolo [4,5-
f] -1,2-benzisoxazol-6-one; 5,
7-dihydro-3- [3- [1- (phenylmethyl)-
4-piperidinyl] propyl] -6H-pyrrolo [4,5
-F] -1,2-benzisoxazol-6-one;
6,8-dihydro-3- [2- [1- (phenylmethyl) -4-piperidinyl] ethyl] -7H-pyrrolo [5,4-g] -1,2-benzisoxazole-7-
On; and 5,7-dihydro-3- [3- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-
Pyrrolo [4,5-f] -1,2-benzisoxazol-6-one.

In a most preferred embodiment of the present invention, the compound of the formula (1) is 5,7-dihydro-3- [3
-[1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,2-benzisoxazol-6-one. An eighth aspect of the present invention provides:
Pharmaceutical compositions comprising a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. Preferred compounds of formula (1) are those provided above. The pharmaceutical compositions of the invention are those suitable for oral, rectal, parenteral (intravenous, intramuscular), transdermal, buccal, nasal, ocular, sublingual, topical, or subcutaneous administration. This embodiment further encompasses a dosage form of the compound of Formula (1), or a pharmaceutically acceptable salt or solvate thereof, such as a tablet, troche, dispersion, suspension, Such as, but not limited to, solutions, capsules, and patches. Preferred compounds of formula (1) are those provided above. The pharmaceutical compositions and dosage forms of the present invention are particularly suitable for treating age-related behavioral disorders in companion animals.

Definitions As used herein, the term "treatment of age-related behavioral disorders" refers to one of the cognitive impairments found in age-related behavioral disorders.
Or to treat, control, prevent, and / or reduce any or more signs (ie, symptoms). Age-related disorders include, but are not limited to, cognitive dysfunction syndrome and degenerative depressive symptoms (also referred to as age-related cognitive and affective disorders). Symptoms of age-related behavioral disorders include, but are not limited to, those of cognitive dysfunction syndrome.

As used herein, the term "cognitive dysfunction syndrome" refers to an animal that cannot be attributed to a non-cognate general medical condition, such as tissue overgrowth, infection, or organ failure. Means age-related decline in cognitive ability. Symptoms of cognitive dysfunction syndrome include, but are not limited to, memory loss, which may be disorientation and / or confusion, altered interactions with family members, sleep-wake cycles, It begins with changes, reduced activity levels, and the onset of inappropriate voiding. The term further includes the symptoms described in the following literature: Ruehl,
WW) et al., Psychopharmacology of Animal Behavior Di
sorders (Psychopharmacology of Animal Behavioral Disorders), compiled by Dodman, NH and Shuster, L. (Boston, 1998) 283-304; Neilson, JC et al., JAVA 210 (8): 1129.
-1134 (1997); Ruehl, WW
Prog. Brain Res. 106: 217-225 (199
5); and Ruehl, WW et al., Adv. Pharma.
col. 42: 316-319 (1998); all of which are incorporated herein by reference.

[0028] As used herein, the term "treatment of cognitive dysfunction syndrome" means reducing the severity of one or more symptoms associated with cognitive dysfunction syndrome. Symptoms of degenerative depression include, but are not limited to, symptoms of depression, drowsiness, and symptoms of cognitive impairment syndrome.

[0029] As used herein, the term "improving the cognitive process" means improving the ability of a pet to learn a new job or to perform a previously learned job. I do.

[0030] As used herein, the term "treatment of amnesia" refers to a pet animal recalling, for example, an object, a spatial relationship, a human or other animal, or a task previously learned. Means to improve the ability to perform.

As used herein, the term "treatment of disorientation or confusion" refers to, for example, that a pet animal appears to be degaussed, wanders unintentionally, and voices without translation. Means to extinguish or tend to stare at the sky or the wall.

[0032] As used herein, the term "improving sociability" refers to a patient, for example, trying to draw the attention of a family member or to greet a family member appropriately. Means to increase the tendency.

As used herein, the term “sleep-
"Adjustment of wakefulness" refers to increasing a patient's tendency to sleep at night, decreasing a patient's tendency to sleep during the day,
Alternatively, it means reducing the tendency of the patient to wander or go around the clock for 24 hours a day.

As used herein, the terms "improving discipline indoors" and "treating inappropriate excretion" refer to, for example, when a pet animal urinates or defecates indoors. Means to urinate or defecate indoors immediately before a family member, or to urinate or defecate immediately after entering the room indoors from outside. For pets that previously signaled that they wanted to go outdoors, this term means improving the frequency with which pets signaled that they wanted to go outdoors.

As used herein, the term “memory-enhancing effective amount” refers to an object, learned work, positional relationship, human (eg, a family member), when administered to a pet animal.
Or the amount of a compound that increases the ability of an animal to recall another animal. A memory-enhancing effective amount of a compound or compound mixture can be determined by one or more models known to those of skill in the art. Suitable models include, but are not limited to, the following: Ruehl, WW, et al., Progress Brain Res.
Tipton, KF and Boult
on, AA) Editing (Esrubier Science, 1995)
217-224; Head, E. et al., Behavioral N
euroscience 109: 851-858 (1995); and Head (E.) et al., Prog. Neuro-Psychopharma.
col. & Biol. Psychiatry 20 (5): 15-530
(1996).

As used herein, the term “acetylcholinesterase-inhibiting effective amount” means the amount of a compound that inhibits the biological activity of acetylcholinesterase in vivo or in vitro. The term comes from healthy animals,
Similarly, it refers to inhibition of acetylcholinesterase isolated from animals exhibiting symptoms of cognitive impairment syndrome. The term also refers to inhibition of acetylcholinesterase isolated from both brain and skeletal muscle.

As used herein, the term “pharmaceutically acceptable salt” refers to non-toxic acid addition salts, ie, salts containing a pharmaceutically acceptable anion, such as, but not limited to Not limited, but hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid Citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharinate, benzoate, methanesulfonate, ethanesulfonate,
Means benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis (2-hydroxy-3-naphthoate), etc. Suitable pharmaceutically acceptable salts Is maleate.

[0038]

The present invention is based on the discovery that acetylcholinesterase inhibitors are effective in treating age-related behavioral disorders in dogs and cats. Age-related behavioral disorders include, but are not limited to, cognitive dysfunction syndrome (CDS) and degenerative depressive symptoms. Preferred acetylcholinesterase inhibitors are those represented by formula (1). Of these,
Icopezil, ie, 5,7-
Dihydro-3- [3- [1- (phenylmethyl) -4-
Piperidinyl] ethyl] -6H-pyrrolo [4,5-f]
-1,2-Benzisoxazol-6-one maleate is most preferred.

As described above, the cause of age-related behavioral disorders such as CDS is unknown. Unexpectedly, the present inventors have discovered that administration of an acetylcholinesterase inhibitor, such as a compound of formula (1), can treat the age-related disorder. Without being limited by theory
It is presently believed that CDS and related disorders can be treated by increasing cholinergic transmission in the brain of affected animals and increasing acetylcholine levels. It is further believed that it can inhibit the biological activity of acetylcholinesterase, a protein that catalyzes the degradation of acetylcholine, thereby increasing acetylcholine levels in the brain and increasing cholinergic transmission. Thus, the present invention relates to patients suffering from age-related behavioral disorders (ie,
Companion animal) with a memory-enhancing effective amount or an acetylcholinesterase-inhibiting effective amount of an acetylcholinesterase inhibitor.

The preparation of acetylcholinesterase inhibitors suitable for use in the methods and compositions of the present invention is described in US Pat. Nos. 5,750,542 and 5,53.
No. 8,984, and WO 92/17475, all of which are incorporated herein by reference.
The ability of these compounds to inhibit acetylcholinesterase activity can be determined by various standard tests known to those skilled in the art. See, for example, Mimori,
Y.) et al., Behav. Brain Res. 83: 25-30 (199).
7); and Ellman, GL et al., Biochem.
harm. 7: 88-95 (1960). Their effectiveness in age-related behavioral disorders such as CDS can be quantified by the methods described below and methods known to those skilled in the art. See also: Ruehl, WW et al., Progress Brain Res. Tipton, KFand Boulton, A.
A.) Editing (Esrubier Science, 1995) 217
~ 224.

Pharmaceutical Formulations and Therapeutic Methods The compound represented by formula (1) and a pharmaceutically acceptable salt thereof (hereinafter, referred to as the "compound of the present invention") can be used in various ways to treat patients (ie, age-related behaviors such as CDS). (A pet animal suffering from a disorder). These methods include, but are not limited to, oral administration by capsule or tablet, parenteral administration by sterile solution or suspension, and intravenous administration by solution. The free base compounds of the present invention can be formulated and administered in the form of their pharmaceutically acceptable acid addition salts.

A suitable daily dose of the compounds of the invention will generally be from about 0.001 to about 5 mg / k for the average pet.
g / day, optionally about 0.005 to 1 mg / k
g / day, and preferably about 0.01 to about 0.50 m
g / kg / day, which can be administered in single or divided doses. These dosages are encompassed by the phrases "therapeutically effective amount,""memory-enhancingamount,""acetylcholinesterase inhibitory amount," and "sufficient amount to improve the cognitive process," as used herein.

The compounds of the present invention, when incorporated in a solution or suspension for parenteral administration, have a concentration of at least 1% by weight, preferably about 4 to about 70% by weight (based on total unit weight). is there. A typical parenteral dosage unit comprises from about 0.001 to about 100 mg of a compound of the present invention.

The compounds of the present invention may be administered orally with an inert diluent or an edible carrier, or enclosed in gelatin capsules or compressed into tablets. These formulations generally contain at least 0.1% of a compound of the present invention. A typical oral dosage unit is about 0.
001 mg to about 100 mg.

The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the routes set forth above. Such administration is performed once or more than once. The compound can be administered in a variety of different dosage forms; that is, the compound is combined with a variety of pharmaceutically acceptable inert carriers, tablets, capsules, lozenges, troches, powders, sprays, creams, waxes. It can be combined in the form of salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, solutions for injection, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Further, the oral pharmaceutical compositions may be suitably sweetened and / or flavored. Generally, the compound will be present in such dosage forms at a concentration level ranging from about 5.0% to about 70% by weight.

Tablets for oral administration can contain various excipients, for example
Various disintegrants, including microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine, such as starch (preferably, corn, potato or tapioca starch), alginic acid and certain complex silicates And the like are employed with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Lubricants, surfactants, and lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc, are also useful for tablet preparation purposes. Solid compositions of a similar type may be employed as fillers in gelatin capsules. Suitable fillers include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds may contain various sweetening or flavoring agents, colorings or dyes and, if desired, also emulsifying and / or suspending agents.
It can be combined with diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof.

In addition to the common dosage forms described above, the compounds of the present invention are administered by controlled release means and / or delivery devices capable of releasing the compounds in the required proportions, maintaining a constant pharmacological effect for the required amount of time. be able to. Such dosage forms provide the body with the drug for a period of time and maintain the therapeutic range of drug levels for a longer period of time than conventional uncontrolled formulations. Suitable controlled release pharmaceutical compositions and delivery devices suitable for the administration of the compounds of the present invention are described in U.S. Patent Nos. 3,847,770; 3,916,899; 3,536,809; 3,598. No. 3,630,200; No. 4,008,719; No. 4,687,610; No. 4,769,027; No. 5,674,533; No. 5,059,595. No. 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,566; and 5,733,566. And the disclosures of which are incorporated herein by reference. For example, the compounds are a class of biodegradable polymers useful for achieving controlled release of a drug, such as polylactic acid, polyglycolic acid, polylactic / polyglycolic acid copolymer, polyepsin caprolactone, polyhydroxybutyric acid, polyorthobutyric acid. It may be attached to crosslinked or amphiphilic block copolymers of esters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels and the like.

Aqueous and non-aqueous solutions, and suspensions and mixtures thereof may be used for parenteral administration of the compounds of the present invention. For example, the compounds of the present invention can be dissolved in oils, such as sesame or peanut oil, or in water, or in aqueous propylene glycol. Although not always necessary, aqueous solutions can be suitably buffered, as is well known in the art.
The liquid diluent is preferably isotonic for use. These aqueous solutions are suitable for intravenous injection. The oil solutions are suitable for intra-articular, intramuscular and subcutaneous injection. Preparation of all these solutions under sterile conditions can be readily carried out by standard pharmaceutical techniques well known to those skilled in the art.

The compounds of the present invention can be administered topically. Topical administration may be carried out as creams, jellies, gels, pastes, patches, ointments and the like in accordance with normal pharmaceutical practice. The compounds may also be administered in animal feed or as a drinking composition.

The compounds may also be in the form of liposome delivery systems, for example, small single membrane vesicles, large single membrane vesicles,
And it may be administered as multilayer thin film vesicles. Liposomes contain various phospholipids, such as cholesterol,
It can be formed from stearylamine or phosphatidylcholine and the like.

The compound may also be bound to a soluble polymer as the drug carrier of interest. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenyl, polyhydroxyethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Further, new aspects of the present invention will be described in the following examples.

[0052]

EXAMPLE 1 Determination of CDS and Its Therapeutic Efficacy Using a Questionnaire To determine if a dog has CDS and if the dose of a particular compound of the invention is efficacious. One method is to utilize a checklist designed to track changes in patient behavior over time. An appropriate checklist is shown in Table 1.

[0053]

[Table 1]

If the dog is over about 7 years old (or young but large breed dog) and exhibits one or more signs of the category, CDS should be considered, All mental and neurological tests should be performed. If the results of the study do not reveal other causes of the patient's symptoms, additional screening in diagnostic laboratories may be appropriate to identify other non-cognate medical symptoms contributing to the clinical signs can do. If no non-cognate medical symptoms are found, treatment with a compound of the present invention may be commenced. A chart similar to that shown in Table 1 can then be used to determine the effectiveness of the treatment.

Example 2 Determination of CDS and Its Therapeutic Efficacy Using Spatial Memory Model The inter-subject design using a laboratory model for spatial memory is used to determine the efficacy of the compound of the present invention in treating canine CDS. For example, the general efficacy of icopezil can be tested in this way.

For the appropriate model, see Head,
E.) et al. (Prog. Neuro-Psychopharmacol.
& Biol. Psychiatry 20 (5): 15-530 (19
96). This model is susceptible to age-dependent cognitive impairment and the compounds of the invention can increase or can be used to assess that ability. See: Head, E. et al., Behavioral Neuroscience 109:
851-858 (1995). According to this model, aging dogs exhibit the disadvantage of very slow learning and behavior. Aged dogs with impaired cognition can, for example, act within the range of normal dogs with a small delay (eg, 20 seconds) rather than a long delay (eg, 70-110 seconds). In this test, the behavior of age-related dogs is improved by the administration of sergiline chloride.

Other models known to those skilled in the art can also be applied to test the efficacy of the compounds of the present invention in treating CDS in both dogs and cats. Indeed, the invention is not limited to the above examples and details, the scope of which is further defined by the claims appended hereto.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 25/28 A61P 25/28 C07D 498/04 103 C07D 498/04 103

Claims (21)

[Claims] 1. A method of treating an age-related behavioral disorder in a companion animal, comprising administering to the companion animal in need of such treatment a therapeutically effective amount of an acetylcholinesterase inhibitor. 2. The method of claim 1, wherein said age-related behavioral disorder is cognitive dysfunction syndrome or degenerative depression. 3. A method for improving the recognition process of a pet animal, which comprises administering to a pet animal in need of such improvement an amount of acetylcholinesterase inhibitor sufficient to improve the recognition process. Method. 4. A method of treating amnesia in a companion animal, comprising administering to the companion animal in need of such improvement an acetylcholinesterase inhibitor in an amount sufficient to improve the cognitive process. Method. 5. A method for treating disorientation or confusion in a companion animal, comprising administering to the companion animal in need of such treatment a therapeutically effective amount of an acetylcholinesterase inhibitor. 6. A method of improving the social character of a companion animal, comprising administering to the companion animal in need of such improvement a therapeutically effective amount of an acetylcholinesterase inhibitor. 7. A method of adjusting the sleep-wake cycle of a companion animal, comprising administering to the companion animal in need of such adjustment a therapeutically effective amount of an acetylcholinesterase inhibitor. 8. A method of treating inappropriate excretion of a companion animal, comprising administering to the companion animal in need of such treatment a therapeutically effective amount of an acetylcholinesterase inhibitor. 9. The method according to claim 1, wherein the pet animal is a cat or a dog. 10. The acetylcholinesterase-in.
The compound wherein the inhibitor is represented by the following formula (1):
10. A commercially acceptable salt or solvate thereof.
Method listed:[However, in the formula, R¹And R²Are each independently water
Element, (C₁-C₆) Alkoxy, benzyloxy,
Nonoxy, hydroxy, phenyl, benzyl, halo, nitro
B, cyano, -COR⁵, -COOR⁵, -CONHR
⁵, -NR⁵R⁶, -NR⁵COR⁶, -OCONR⁵
R⁶, -NHCOOR⁵, (C₁-C₆) Alkyl
Alkyl is substituted by 1 to 3 fluorine atoms
), SO_pCH ₂-Phenyl or SO
_p(C₁-C₆) Alkyl wherein p is 0, 1 or
2) pyridylmethyloxy or thienylmethyloxy
Si, 2-oxazolyl, 2-thiazolyl, and benze
Selected from the group consisting of sulfonamides;
The phenoxy, benzyloxy, phenyl, benzyl
And the phenyl moiety of the benzenesulfonamide group,
Pyridylmethyloxy or thienylmethyloxy group
Pyridyl and thienyl moieties, and the 2-oxazo
Oxazolyl and thia of the ril and 2-thiazolyl groups
The zolyl moiety is halo, (C₁-C₄) Alkyl, trif
Fluoromethyl, (C₁-C₄) Alkoxy, cyano, d
Independently selected from the group consisting of toro and hydroxy
May be substituted by one or two substituents;
Or R¹And R²Binds to adjacent carbon atoms and
Together with the carbon atom to which is attached, formula (2):(However, in the formula, R³Is hydrogen or (C₁-C₆) Al
Kill; J is oxygen, sulfur or NR⁴R⁴Is hydrogen or
Is (C₁-C₄) Alkyl; and Q is oxygen, sulfur,
NH, CHCH₃, C (CH₃)₂, -CH = CH-,
Or (CH₂) ₁Wherein l is an integer of 1 to 3
X is oxygen or io
Y is-(CH₂)_m-, -CH = CH (CH
₂)_n-, -NR⁴(CH₂)_m-Or -O (CH
₂)_mWherein n is an integer of 0 to 3, and m is
An integer from 1 to 3; R⁵And R⁶Is German
First, hydrogen, (C₁-C₆) Alkyl, phenyl, and
And benzyl; provided that the phenyl and
And the phenyl moiety of the benzyl group is fluoro, chloro,
Mo, iodine, (C₁-C₄) Alkyl, trifluorome
Chill, (C₁-C₄) Alkoxy, cyano, nitro and
One or more independently selected from the group consisting of
May be substituted by two substituents; or
NR⁵R⁶Together form a four- or five-membered ring
Wherein one atom of the ring is nitrogen and the other is carbon.
Nitrogen, oxygen or nitrogen; or NR⁵COR⁶Haichi
L to form a 4- to 5-membered lactone ring; L
Is phenyl, phenyl- (C₁-C₆) Alkyl, syn
Namyl or pyridylmethyl; provided that
Nil and phenyl- (C₁-C₆) Alkyl phenyl
The part is (C₁-C₆) Alkyl, (C₁-C₆) Al
Koxy, (C ₁-C₄) Alkoxycarbonyl, (C₁
-C₆) Alkylcarbonyl, —OCONR⁵R⁶, −
NHCOOR⁵, And halo independently selected
Even if substituted by one to three substituents
Or L is of the formula (3):(Where b is an integer of 1 to 4; R⁹And R
¹⁰Are each independently hydrogen, (C₁-C₄) Archi
And halo, and phenyl; E and F
Are independently -CH- or nitrogen; and G is oxygen, sulfur
Or NR⁴Where E and F are both nitrogen
If so, R⁹And R¹⁰One of which does not exist
And R⁷And R⁸Is
Independently, hydrogen, (C₁-C₆) Alkyl, (C₁−
C₆) Alkoxycarbonyl, (C₁-C₆) Alkyl
Carbonyl, and (C₁-C₆) Consisting of alkoxy
Selected from the group; provided that (C₁-C₆) Arco
Xy shall not be bound to the carbon adjacent to the nitrogen
]. 11. The method according to claim 10, wherein the compound represented by the formula (1) is selected from the group consisting of the following compounds: 5,7-dihydro-7-methyl-3- [2- [1-
(Phenylmethyl) -4-piperidinyl] ethyl] -6
H-pyrrolo [4,5-f] -1,2-benzisoxazol-6-one; 5,7-dihydro-7-ethyl-3-
[2- [1- (phenylmethyl) -4-piperidinyl]
Ethyl] -6H-pyrrolo [4,5-f] -1,2-benzisoxazol-6-one; 5,7-dihydro-3-
[2- [1- (2-chloro-5-thiophenemethyl)-
4-piperidinyl] ethyl] -6H-pyrrolo [4,5-
f] -1,2-benzisoxazol-6-one; 5,
7-dihydro-3- [2- [1- (2-methyl-4-thiazolmethyl) -4-piperidinyl] ethyl] -6H
-Pyrrolo [4,5-f] -1,2-benzisoxazol-6-one; 3- [2- [1- (3-bromophenylmethyl) -4-piperidinyl] ethyl] -5,7- Dihydro-6H-pyrrolo [4,5-f] -1,2-benzisoxazol-6-one; 3- [2- [1- (4-bromophenylmethyl) -4-piperidinyl] ethyl]-
5,7-dihydro-6H-pyrrolo [4,5-f] -1,
2-benzisoxazol-6-one; 5,7-dihydro-3- [3- [1- (phenylmethyl) -4-piperidinyl] propyl] -6H-pyrrolo [4,5-f]-
1,2-benzisoxazol-6-one; 6,8-dihydro-3- [2- [1- (phenylmethyl) -4-piperidinyl] ethyl] -7H-pyrrolo [5,4-g]-
1,2-benzisoxazol-7-one; and 5,
7-dihydro-3- [3- [1- (phenylmethyl)-
4-piperidinyl] ethyl] -6H-pyrrolo [4,5-
f] -1,2-Benzisoxazol-6-one. 12. The compound of the formula (1) is 5,7-dihydro-3- [3- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f]- 1,
12. A benzisoxazol-6-one.
The described method. 13. Treating an age-related behavioral disorder in a companion comprising a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. Pharmaceutical composition used for 14. The pharmaceutical composition according to claim 13, wherein the compound represented by the formula (1) is selected from the group consisting of the following compounds: 5,7-dihydro-7-methyl-3- [2-
[1- (Phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,2-benzisoxazol-6-one; 5,7-dihydro-7-ethyl-3 -[2- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,
2-benzisoxazol-6-one; 5,7-dihydro-3- [2- [1- (2-chloro-5-thiophenmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5 -F] -1,2-benzisoxazole-6
ON; 5,7-dihydro-3- [2- [1- (2-methyl-4-thiazolemethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,2-benz Isoxazol-6-one; 3- [2- [1- (3-bromophenylmethyl) -4-piperidinyl] ethyl]-
5,7-dihydro-6H-pyrrolo [4,5-f] -1,
2-benzisoxazol-6-one; 3- [2- [1
-(4-bromophenylmethyl) -4-piperidinyl]
Ethyl] -5,7-dihydro-6H-pyrrolo [4,5-
f] -1,2-benzisoxazol-6-one; 5,
7-dihydro-3- [3- [1- (phenylmethyl)-
4-piperidinyl] propyl] -6H-pyrrolo [4,5
-F] -1,2-benzisoxazol-6-one;
6,8-dihydro-3- [2- [1- (phenylmethyl) -4-piperidinyl] ethyl] -7H-pyrrolo [5,4-g] -1,2-benzisoxazole-7-
On; and 5,7-dihydro-3- [3- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-
Pyrrolo [4,5-f] -1,2-benzisoxazol-6-one. 15. The compound of the formula (1) is 5,7-dihydro-3- [3- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f]- 1,
15. It is 2-benzisoxazol-6-one.
The pharmaceutical composition according to any one of the preceding claims. 16. The method according to claim 16, wherein the pharmaceutical composition is oral, rectal, parenteral,
14. The pharmaceutical composition according to claim 13, which is suitable for transdermal, buccal, nasal, ocular, sublingual, topical, or subcutaneous administration. 17. A dosage form of a compound of formula (1) for use in treating age-related behavioral disorders in companion animals. 18. The dosage form according to claim 17, wherein said dosage form is a tablet, troche, dispersion, suspension, solution, capsule, or patch. 19. The dosage form according to claim 18, wherein the compound represented by the formula (1) is selected from the group consisting of the following compounds: 5,7-dihydro-7-methyl-3- [2- [1
-(Phenylmethyl) -4-piperidinyl] ethyl]-
6H-pyrrolo [4,5-f] -1,2-benzisoxazol-6-one; 5,7-dihydro-7-ethyl-3
-[2- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,2-
Benzisoxazol-6-one; 5,7-dihydro-
3- [2- [1- (2-Chloro-5-thiophenemethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,2-benzisoxazole-6
ON; 5,7-dihydro-3- [2- [1- (2-methyl-4-thiazolemethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f] -1,2-benz Isoxazol-6-one; 3- [2- [1- (3-bromophenylmethyl) -4-piperidinyl] ethyl]-
5,7-dihydro-6H-pyrrolo [4,5-f] -1,
2-benzisoxazol-6-one; 3- [2- [1
-(4-bromophenylmethyl) -4-piperidinyl]
Ethyl] -5,7-dihydro-6H-pyrrolo [4,5-
f] -1,2-benzisoxazol-6-one; 5,
7-dihydro-3- [3- [1- (phenylmethyl)-
4-piperidinyl] propyl] -6H-pyrrolo [4,5
-F] -1,2-benzisoxazol-6-one;
6,8-dihydro-3- [2- [1- (phenylmethyl) -4-piperidinyl] ethyl] -7H-pyrrolo [5,4-g] -1,2-benzisoxazole-7-
On; and 5,7-dihydro-3- [3- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-
Pyrrolo [4,5-f] -1,2-benzisoxazol-6-one. 20. The compound of the formula (1) wherein 5,7-dihydro-3- [3- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f]- 1,
20. It is 2-benzisoxazol-6-one.
The dosage form as described. 21. The dosage form according to claim 20, wherein said dosage form comprises about 0.001 mg to about 100 mg of the compound represented by the formula (1).